title: Post-genome-wide association study challenges for lipid traits: describing age as a modifier of gene-lipid associations in the Population Architecture using Genomics and Epidemiology (PAGE) study.
abstract: Numerous common genetic variants that influence plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride distributions have been identified via genome-wide association studies (GWAS). However, whether or not these associations are age-dependent has largely been overlooked. We conducted an association study and meta-analysis in more than 22,000 European Americans between 49 previously identified GWAS variants and the three lipid traits, stratified by age (males: <50 or ≥50 years of age; females: pre- or postmenopausal). For each variant, a test of heterogeneity was performed between the two age strata and significant Phet values were used as evidence of age-specific genetic effects. We identified seven associations in females and eight in males that displayed suggestive heterogeneity by age (Phet < 0.05). The association between rs174547 (FADS1) and LDL-C in males displayed the most evidence for heterogeneity between age groups (Phet = 1.74E-03, I(2) = 89.8), with a significant association in older males (P = 1.39E-06) but not younger males (P = 0.99). However, none of the suggestive modifying effects survived adjustment for multiple testing, highlighting the challenges of identifying modifiers of modest SNP-trait associations despite large sample sizes.
authors.affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, TN.
authors.forename: Logan
authors.initials: L
authors.lastname: Dumitrescu
authors.forename: Cara L
authors.initials: CL
authors.lastname: Carty
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.forename: Lucia A
authors.initials: LA
authors.lastname: Hindorff
authors.forename: Shelley A
authors.initials: SA
authors.lastname: Cole
authors.forename: Petra
authors.initials: P
authors.lastname: Bůžková
authors.forename: Fredrick R
authors.initials: FR
authors.lastname: Schumacher
authors.forename: Charles B
authors.initials: CB
authors.lastname: Eaton
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Goodloe
authors.forename: David J
authors.initials: DJ
authors.lastname: Duggan
authors.forename: Jeff
authors.initials: J
authors.lastname: Haessler
authors.forename: Barbara
authors.initials: B
authors.lastname: Cochran
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.forename: Iona
authors.initials: I
authors.lastname: Cheng
authors.forename: Karen C
authors.initials: KC
authors.lastname: Johnson
authors.forename: Chris S
authors.initials: CS
authors.lastname: Carlson
authors.forename: Shelly-Ann
authors.initials: SA
authors.lastname: Love
authors.forename: Kristin
authors.initials: K
authors.lastname: Brown-Gentry
authors.forename: Alejandro Q
authors.initials: AQ
authors.lastname: Nato
authors.forename: Miguel
authors.initials: M
authors.lastname: Quibrera
authors.forename: Garnet
authors.initials: G
authors.lastname: Anderson
authors.forename: Ralph V
authors.initials: RV
authors.lastname: Shohet
authors.forename: José Luis
authors.initials: JL
authors.lastname: Ambite
authors.forename: Lynne R
authors.initials: LR
authors.lastname: Wilkens
authors.forename: Loïc Le
authors.initials: LL
authors.lastname: Marchand
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.forename: Steven
authors.initials: S
authors.lastname: Buyske
authors.forename: Charles
authors.initials: C
authors.lastname: Kooperberg
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
authors.forename: Myriam
authors.initials: M
authors.lastname: Fornage
authors.forename: Dana C
authors.initials: DC
authors.lastname: Crawford
mesh_terms: D000328:Adult; D000368:Aged; D000090943:Delta-5 Fatty Acid Desaturase; D005260:Female; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D006801:Humans; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: D000090943:Delta-5 Fatty Acid Desaturase; D008055:Lipids; C000716847:FADS1 protein, human
keywords: PAGE; age; genetic association; lipids; modifier